Treatment for Chronic Myocardial Infarct

ABSTRACT

A method of treating chronic post-myocardial infarction including helical needle transendocardial delivery of autologous bone marrow (ABM) mononuclear cells around regions of hypo or akinesia in chronic post-myocardial infarction (MI) patients. The treatment is safe and improves ejection fraction (EF).

This application is a continuation of U.S. application Ser. No.11/735,869 filed Apr. 16, 2007, now U.S. Pat. No. 8,496,926

FIELD OF THE INVENTIONS

The inventions described below relate the field of cardiology.

BACKGROUND OF THE INVENTIONS

Chronic Myocardial Infarction refers to myocardial tissue which has diedas the result of myocardial infarct, and has over the course of timebecome remodeled to scar tissue within the myocardium. Left untreated,myocardial infarction induces global changes in the ventriculararchitecture in a process called ventricular remodeling. Eventually, thepatient experiences ventricular dilation and ventricular dysfunction.This ventricular remodeling is a major cause of heart failure.

While there are several suggested means of ameliorating the effects ofacute myocardial infarction (immediately after the event leading toinfarct), no significant therapy has been proposed or implemented forthe amelioration or reversal of chronic myocardial infarction and thedeleterious effects of infracted tissue after substantial transformationor remodeling of the infracted tissue to scar tissue.

SUMMARY

The method of treating chronic myocardial infarction described belowcomprises injection of autologous bone marrow derived mononuclear cells,or cells derived from those mononuclear cells, into the myocardium.These cells are injected near or in the chronic infracted tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing improvement in ejection fraction of thepatients in an experimental group, after injection of autologous bonemarrow derived mononuclear cells.

FIG. 2 is a graph showing improvement in exercise tolerance of thepatients in an experimental group, after injection of autologous bonemarrow derived mononuclear cells.

FIG. 3 is a graph showing improvement in ventricular diastolic volume ofthe patients in an experimental group, after injection of autologousbone marrow derived mononuclear cells.

DETAILED DESCRIPTION OF THE INVENTIONS

Chronic myocardial infarction refers to the condition of infractedtissues after the infracted tissue has been remodeled by natural woundhealing responses and comprises, after such remodeling, scar tissue,which is substantially dead. This is distinct from ischemic tissuecharacteristic of chronic ischemia, which refers to tissue which ischronically hypoxic due to lack of sufficient blood flow, but is stillviable even if not fully active in the muscular andelectro-physiologically activity of the heart. The method starts withidentifying patients afflicted with chronic myocardial infarction. Oncepatients with chronic myocardial infarction are identified, theirsuitability for treatment under the method currently requires a lowejection fraction (less that about 40%). In our experiments aimed atdetermining if the treatment is safe, we included patients with leftventricular dysfunction (less that about 40% but not less than about30%) that were not candidates for ventricular aneurysm surgery,implantable defibrillators, or valve repair or replacement, whileexcluding patients with active infections, malignancies, high gradeatrioventricular block, sustained ventricular tachyarrythmias, a recentMI (less than 4 weeks old), presence of an artificial aortic valve,recent history of alcohol or drug abuse or evidence of othermulti-system disease. However, given the results of our experiments, weexpect that the treatment could benefit all patients suffering fromchronic myocardial infarction so long as they can tolerate theprocedure.

Immediately prior to the catheterization necessary to delivery theautologous bone marrow cells, the cells are collected from suitablesites within the patient, such as the posterior iliac crest, vertebralbody and/or sternum. Bone marrow mononuclear cells are isolated bysuitable methods such as density gradient on Ficoll-Paque Plus tubes (GEHealthcare, UK) through 100 μm nylon mesh to remove cell aggregates, andre-suspended in Ringers solution at a concentration of 1×10⁸ cells/ml ina total volume of 1.3 ml. These cells are prepared for injection backinto the patient within about 4 to 6 hours after harvesting. The bonemarrow derived mononuclear cells include CD-34 positive cells, CD-133positive cells, and CD-90 positive cells (mesenchymal stem cells) whichmay also be separately isolated for injection to treat chronicmyocardial infarction. Preferably at least 40% of the cells isolatedcomprise CD-34 positive cells, CD-90 positive cells, and CD-133 positivecells or a combination thereof.

Just prior to cell delivery, the doctors performing the cell deliveryuse various techniques, including ECG's, echocardiography, and baselineorthogonal ventriculography data to define the target infarct tissuezones. Access to the target infarct zone is preferably via catheter,transendocardially (with the catheter tip in the endocardial space) intothe myocardium. Intramyocardial delivery may also be accomplishedthrough a trans-coronary venous approach as described in BioCardia'sU.S. Pat. No. 6,585,716, through a trans-coronary arterial approach, ora trans-epicardial approach. Any suitable catheter system can be used,though the BioCardia™ helical infusion catheter and steerable guidecatheter are particularly well suited to the method. Dosage may rangefrom three injections of 0.1 to 0.2 ml of cell solution at aconcentration of 10⁸ (one hundred million) cells/ml (totaling about5×10⁷ cells) to 11 injections of 0.1 to 0.2 ml of cell solution at aconcentration of 1.2×10⁸ cells/ml for a total of 1.2×10⁸ cells spreadover numerous injection cites proximate the target infarct tissue. Thesolution containing the cells is injected near or at the site of aninfarct, in several small injections proximate the target infarct. Eachinjection is performed slowly, and the helical injection catheter isleft in the injection site to dwell for a substantial period (about 15to 30 seconds) to prevent back-leakage of the solution into theendocardial space of the ventricle.

The efficacy of the treatment is reflected in FIGS. 1 through 3, whichshow that chronic myocardial infarct patients treated with autologousbone marrow derived mononuclear cells benefit from improved ejectionfraction, improved exercise tolerance, and reduced ventricular dilation.As shown in FIG. 1, ejection fraction of the patients, as measured by 2Dechocardiography, demonstrates a statistically significant increase at 1week (P=0.02), 12 weeks (P=0.01), 6 months (P=0.001), and 12 months(P=0.0001) as compared to baseline. All patients in the experimentalgroup showed an increase in this parameter over baseline at 6 months and12 months. Smaller long term improvements in diastolic volume andexercise tolerances were noted in our experimental group, as shown inFIGS. 2 and 3. Given the results of our experiment with a small numberof patients, the method results in significantly improved ejectionsfraction, reduced ventricular dilation, and improved exercise tolerance.No increase in ventricular arrhythmias was detected in any patient inthe experimental group.

Peripheral blood derived mononuclear cells (PBMC) and adipose tissuederived mononuclear cells can be also be used in the treatment, as cancells derived from those mononuclear cells harvested from the peripheralblood or adipose tissue. While the preferred embodiments of the devicesand methods have been described in reference to the environment in whichthey were developed, they are merely illustrative of the principles ofthe inventions. Other embodiments of the method, including sources ofcells and methods of isolation, and particular constituent cells of theinjected cell population may be devised without departing from thespirit of the inventions and the scope of the appended claims.

We claim:
 1. A method of treating chronic myocardial infarctioncomprising: identifying a patient with chronic myocardial infarctionwith areas of chronic myocardial infarct within the patient'smyocardium; harvesting autologous bone marrow cells from the patient;concentrating cells from the autologous bone marrow to form atherapeutic preparation of mononuclear cells comprising CD-34 positivecells and CD-133 positive cells; injecting the therapeutic preparation,at a level of 30,000,000 to 264,000,000 of the concentrated mononuclearcells into the myocardium of the patient proximate an area of chronicinfarcted tissue resulting from chronic myocardial infarct, where saidinjecting is accomplished transendocardially.
 2. A method of treatingchronic myocardial infarction comprising: identifying a patient withchronic myocardial infarction with areas of chronic myocardial infarctwithin the patient's myocardium; harvesting autologous bone marrow cellsfrom the patient; concentrating cells selected from the group comprisingCD-34 positive cells and CD-133 positive cells from the autologous bonemarrow cells, and suspending said concentrated cells in solution to forma therapeutic preparation; injecting the therapeutic preparation intothe myocardium of the patient proximate areas of chronic myocardialinfarct, where said injecting is accomplished transendocardially.
 3. Themethod of claim 1 further comprising the step of: concentrating thecells from the autologous bone marrow to form a therapeutic preparationof the cells, said therapeutic preparation comprising at least 40% CD-34positive cells, CD-90 positive cells, or CD-133 positive cells or acombination thereof.
 4. The method of claim 1 further comprising thestep of: isolating the cells from the autologous bone marrow to form atherapeutic preparation of the cells, said therapeutic preparationcomprising at least 40% CD-34 positive cells.
 5. The method of claim 1further comprising the step of: isolating the cells from the autologousbone marrow to form a therapeutic preparation of the cells, saidtherapeutic preparation comprising at least 40% CD-133 positive cells.6. The method of claim 2 further comprising the step of: concentratingthe cells from the autologous bone marrow to form a therapeuticpreparation of the cells, said therapeutic preparation comprising atleast 40% CD-34 positive cells, CD-90 positive cells, or CD-133 positivecells or a combination thereof.
 7. The method of claim 2 furthercomprising the step of: concentrating the cells from the autologous bonemarrow to form a therapeutic preparation of the cells, said therapeuticpreparation comprising at least 40% CD-34 positive cells.
 8. The methodof claim 2 further comprising the step of: isolating the cells from theautologous bone marrow to form a therapeutic preparation, saidtherapeutic preparation of the cells comprising at least 40% CD-133positive cells.
 9. The method of claim 2 further comprising the step of:concentrating the cells to form a therapeutic preparation, saidtherapeutic preparation with concentration of CD-34 positive cells,CD-133 positive cells or a combination thereof in the range of 10⁸concentrated cells/ml of solution to 1.2×10⁸ concentrated cells/ml ofsolution.